Abstract
The molecular progression of endometrial cancer is poorly understood, and both genetic and epigenetic factors play a role. Survivin is a member of the inhibitor of apoptosis (IAP) gene family and contains a canonical CpG island that has been described as epigenetically regulated. As survivin is overexpressed in endometrial tumors, we hypothesized that hypomethylation could explain this expression pattern. Surprisingly, methylation-specific PCR and pyrosequencing showed that survivin was hypermethylated in endometrial tumors and correlated with increased survivin expression. We speculated that methylation could inhibit the binding of p53, a repressor of survivin expression. Our data indicates that demethylation of the survivin promoter by decitabine results in p53-dependent survivin repression and that p53 binding can be inhibited by DNA methylation. We are the first to report survivin de-repression by DNA methylation. We also present microarray data, which suggest that de-repression by methylation is a general mechanism of p53 regulation. Demethylation induced by decitabine is traditionally thought to be active in tumors by allowing the re-expression of tumor suppressor genes. However, our results indicate that an additional important mechanism is to decrease the expression of oncogenes.
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Acknowledgements
We thank Dr Pierre Esteve (New England Biolabs) for generously providing the primer sequences for the Survivin methylation-specific PCR assay, Dr Jean-Pierre Issa and Dr Lanlan Shen (MD Anderson Cancer Center) for designing the survivin pyrosequencing assay and Dr Karen Lu (MD Anderson Cancer Center) and Dr James Pickar (Wyeth Research, Philadelphia, PA, USA) for providing endometrial RNA samples.
This study was supported by Grant NIH 1P50CA098258-01 (SPORE in Endometrial Cancer), and a Rosalie B Hite Graduate Student Fellowship.
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Nabilsi, N., Broaddus, R. & Loose, D. DNA methylation inhibits p53-mediated survivin repression. Oncogene 28, 2046–2050 (2009). https://doi.org/10.1038/onc.2009.62
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DOI: https://doi.org/10.1038/onc.2009.62
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